Ubiquitin: everywhere and in every process

It is estimated that approximately 40 thousand proteins are expressed in each cell of the human body. Nevertheless, there is one protein that attracts the interest of researchers and pharmaceutical companies: Ubiquitin. “By the end of the 70s, it was found that this small molecule of 76 amino acids had a fundamental role in the degradation and recycling of proteins”, Mario Rossi, CONICET associate investigator at the Biomedicine Research Institute of Buenos Aires (IBioBA, CONICET- Partner Institute of the Max Planck Society), comments.

Early investigations revealed that when ubiquitin binds to other molecules it triggers a cascade of events that leads the ubiquitin complex to the proteasome, an intracellular complex in charge of degrading proteins to their basic units, the amino acids. Since then, many considerable advances in the study of the ubiquitin signalling and its functions have been made. Besides, researchers identified other molecules with the same characteristics, the Ubiquitin-like proteins (UBLs).

As the ubiquitin, all the UBLs modify their targets after the translation stage, which is the process through which the ARN is decoded in order to synthesize proteins. The binding of different UBL may produce dramatic changes in the function, number and location of target proteins.

“The variety and the possibility of combinations and the regulation posed by the UBLs is bigger than the other posttranslational modifications, and that explains their importance from the point of view of basic science and biotechnology”, Rossi adds.

In broad terms, what happens when proteins are ubiquitinated?

In several cases their structure and function is modified. If we imagine proteins as tools, for instance a hammer, its function will depend on who or where it is used. Posttranslational modifications may modify proteins to direct them towards specific places within the cells or to fulfil well-defined functions. If I add a cap to the hammer, I will be able to hammer a sensitive surface without damaging it. Regarding the binding of ubiquitin to proteins, its most well-known and better characterized function is to label them for degradation.

Based on the number of changes ubiquitin may produce in proteins, which role may this small molecule have as a possible target for different pathologies?

This molecule has a key role in the biology of the cell thanks to the great number of target molecules it has and the number of modifications it can produce. Considering similar experiences with other systems – which intervene in important metabolic or signalling pathways -, it is not wonder that genetic alterations, abnormal expression or dysfunction of the ubiquitination process are related to the occurrence and development of different diseases.

In which pathologies is this process altered? 

The number of investigations on this field is growing, but so far we know it plays a key role in cancer, neurodegenerative pathologies such as Parkinson, immunological diseases, metabolic diseases such as diabetes, cardiovascular problems and viral infections. However, the list is expected to grow as our knowledge of the functioning and regulation of the ubiquitination process is increasing.

What is the mechanism through with ubiquitin ‘labels’ a molecule for degradation or prevents this from happening? 

The ubiquitination process is very complex and involves different types of enzymes. There is one group of enzymes – the E3 ubiquitin ligases – that is directly responsible of binding molecules to the target proteins, forming long chains. The ubiquitins that form these chains bind among themselves through an amino acid called lysine. Each ubiquitin has different lysines that can use to bind to another ubiquitin molecule. In this way, the nature of the signal depends on which lysine is used to enlarge the chain. In the case of the signal that leads the proteins to the proteasome, the ubiquitins bind together through the lysine at position 48.

The number of researchers working on UBLs and ubiquitin is increasing. Which do you believe is the importance of the knowledge generated, not only from the basic science point of view but also from its potential technological use?

I think there are two facts that go hand in hand and mark a turning point in the history of UBLs. Both clearly illustrate the perception of their importance in basic and applied science. On the one hand, in 2003 the use of proteasome inhibitors to inhibit multiple myeloma – a type of cancer – was approved; and on the other hand, the following year Aaron Ciechanover, Avram Hershko and Irwin Rose received the Nobel Prize in Chemistry for the discovery of ubiquitin-mediated protein degradation process. Nowadays we are witnessing the explosion of interest in this topic because it is known that the ubiquitin and the UBLs are involved or altered in different pathologies and they control diverse biological processes. This calls not only researchers that do with basic science and want to understand how these processes work; but also those more interested in the potential applications generated from the knowledge of different fields, ranging from clinic to biotechnology.